Fortilin, p53, and atherosclerosis

Fortilin、p53 和动脉粥样硬化

基本信息

批准号：
8431876
负责人：
Ken Fujise
金额：
$ 37.56万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-15 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8431876
关键词：
3-Dimensional Acute myocardial infarction Amino Acids Apoptosis Apoptotic Applications Grants Arterial Fatty Streak Atherosclerosis Binding Biological Assay Cell Line Cell physiology Cells Cessation of life Cholesterol Coronary Arteriosclerosis Cytokine Signaling Cytosol DNA Fragmentation Death Rate Disease Encapsulated Enzyme-Linked Immunosorbent Assay Exhibits Figs - dietary Flow Cytometry Foam Cells Foundations Genes Genetic Glucans Goals Human Hydroxymethylglutaryl-CoA reductase Infection Infiltration Inflammation Inflammatory Intention Knockout Mice Laboratories Low-Density Lipoproteins Luciferases Malignant Neoplasms Mediating Methods Modeling Molecular Molecular Target Mus Mutate Nature Neoplasms Noxae Nuclear Oral Outcome Pathway interactions Patients Play Production Proliferating Proteins Reagent Regulation Reporting Research Role Serum Small Interfering RNA System TP53 gene TPT1 gene Techniques Testing Time Trauma Tumor Suppressor Proteins United States National Institutes of Health base bench to bedside combat cost cytokine improved macrophage monocyte mortality novel overexpression particle prevent public health relevance small molecule

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this grant proposal entitled "Fortilin, p53, and atherosclerosis" is to define a novel role of fortilin and the fortilin-p53 interaction in atherosclerosis with the intention of establishing anti- fortilin therapy as a viabl strategy against atherosclerosis. By 2025, worldwide death due to atherosclerosis and associated complications is projected to surpass that of every major disease, including cancer, infection, and trauma. The total cost of atherosclerosis-related diseases in the U.S. alone is estimated to be $286 billion annually. After statins, there is no break-through strategy in the pipeline to combat this deadly global disease. Our laboratory has studied fortilin, a 172-amino acid multi-functional protein for the last 15 years. In 2001, we reported for the first time that fortilin protects cells against apoptosis. More recently, we showed that fortilin mediates its anti apoptotic activity through its binding to and inhibition of p53, a tumor suppressor protein. Since (a) p53 protects against not only cancer but also atherosclerosis and (b) fortilin blocks p53, we tested whether the lack of fortilin ameliorated atherosclerosis using Ldlr-/-Apobec1-/- hypercholesterolemic mice, a robust model of atherosclerosis. Strikingly, fortilin+/+Ldlr-/-Apobec1-/- mice had 27 % more atherosclerosis than fortilin+/-Ldlr-/-Apobec1-/- mice with extensive macrophage (M¿) infiltration in the atheroma. In addition, immunostaining showed that fortilin is overexpressed in M¿ and foam cells within human and mouse atherosclerotic lesions. Further, monocytes from patients with coronary atherosclerosis have higher fortilin levels. Finally, we found that hypercholesterolemic sera induce fortilin in M¿. Based on these facts, we hypothesize that (a) pro-atherosclerotic milieu induces fortilin in M¿, (b) M¿-fortilin, when induced, protects M¿ against p53-induced apoptosis, and (c) unchecked M¿ proliferate and produce pro- inflammatory cytokines creating a vicious cycle of inflammation and atherosclerogenesis. The facilitative role of M¿-fortilin through p53 has never been postulated or tested. To test this overall hypothesis, we propose four Specific Aims. In Aim 1, we investigate how fortilin is induced in M¿ and what role induced fortilin plays in M¿, using primary and cell line M¿. In Aim 2, we first define the molecular mechanism by which M-fortilin promotes atherosclerogenesis, using M¿-specific fortilin knockout (KO) mice on the Ldlr-/- Apobec1-/- genetic background (Aim 2.1.). Next, we examine whether fortilin facilitates atherosclerosis through its inhibition of p53, by creating M¿-specific fortilin KO mice on the p53-/-Ldlr-/-Apobec1-/- genetic background (Aim 2.2.). In Aim 3, we expect to show that M¿-specific fortilin silencing re-activates p53 and protects against atherosclerosis by orally administering ¿1,3-D-glucan-encapsulated (GeRP) fortilin siRNA particles to Ldlr-/- Apobec1-/- mice. At the end of the project, we expect M¿-specific anti-fortilin therapy to be found to be a ground-breaking strategy against the deadly and global disease of atherosclerosis.

描述（由申请人提供）：这项题为“Fortilin、p53 和动脉粥样硬化”的资助提案的总体目标是定义 fortilin 以及 fortilin-p53 相互作用在动脉粥样硬化中的新作用，旨在将抗 fortilin 疗法建立为一种治疗方法。对抗动脉粥样硬化的可行策略预计到 2025 年，全球因动脉粥样硬化及相关并发症导致的死亡人数将超过包括癌症、仅在美国，动脉粥样硬化相关疾病的总成本估计就达 2860 亿美元，仅次于他汀类药物，目前尚无突破性策略来对抗这种致命的全球疾病。，一种 172 个氨基酸的多功能蛋白，在过去 15 年中，我们首次报道了 fortilin 可以保护细胞免受凋亡。介导其抗由于 (a) p53 不仅可以预防癌症，还可以预防动脉粥样硬化，并且 (b) fortilin 可以阻断 p53，因此我们使用 Ldlr-/ 测试了缺乏 fortilin 是否可以改善动脉粥样硬化。 -Apobec1-/- 高胆固醇血症小鼠，一种强大的动脉粥样硬化模型。 fortilin+/+Ldlr-/-Apobec1-/- 小鼠的动脉粥样硬化程度比 fortilin+/-Ldlr-/-Apobec1-/- 小鼠多 27%，动脉粥样硬化斑块中有广泛的巨噬细胞 (M¿) 浸润。 M 中过度表达此外，来自冠状动脉粥样硬化患者的单核细胞具有较高的福替林水平。最后，我们发现高胆固醇血清在 M¿ 中诱导福替林水平。基于这些事实，我们认为 (a) 促动脉粥样硬化环境会在 M 中诱导福替林, (b) M¿ -fortilin，当诱导时，保护M¿对抗 p53 诱导的细胞凋亡，以及 (c) 不受控制的 M¿增殖并产生促炎细胞因子，造成炎症和动脉粥样硬化形成的恶性循环。 -fortilin 至 p53 从未被假设或测试过。为了检验这一总体假设，我们提出了四个具体目标，在目标 1 中，我们研究了如何在 M¿ 中诱导 fortilin。诱导福替林在 M 中发挥什么作用，使用原代和细胞系 M¿在目标 2 中，我们首先使用 M¿ 定义了 M-fortilin 促进动脉粥样硬化形成的分子机制。 -Ldlr-/- Apobec1-/- 遗传背景的特异性 fortilin 敲除 (KO) 小鼠（目标 2.1.）接下来，我们检查 fortilin 是否通过产生 M¿ 抑制 p53 来促进动脉粥样硬化。 - p53-/-Ldlr-/-Apobec1-/- 遗传背景上的特异性 fortilin KO 小鼠（目标 2.2.），在目标 3 中，我们期望显示 M¿ -特异性福替林沉默重新激活p53并通过口服预防动脉粥样硬化 ¿ 1,3-D-葡聚糖封装 (GeRP) fortilin siRNA 颗粒作用于 Ldlr-/- Apobec1-/- 小鼠在项目结束时，我们预计 M¿ - 特异性抗福替林疗法被发现是对抗致命的全球性动脉粥样硬化疾病的突破性策略。